Disclosure: Dr. Meagher reports no affiliations with, or financial interests in, any organization that may pose a conflict of interest. This article includes discussion of off-label treatment with atypical antipsychotics.

PP: You led a study1 reviewing the current evidence on pharmacotherapy for delirium. How did the need for this type of study became apparent to you and your co-authors?

DM: In 2006, during a gathering at Duke University, a group of delirium researchers from Europe decided to start the European Delirium Association. Very soon afterward, the American Delirium Society was started. These two organizations have served as a hub to attract delirium researchers and to encourage them to collaborate in their efforts. We’ve gone from perhaps a dozen active researchers 15 years ago to between 200–300 researchers today, which is still a relatively small number considering how common delirium is. For example, delirium occurs in 11%–42% of general hospital inpatients.2 We did the first point prevalence study of delirium in hospitals, which we published in the British Medical Journal.3 In that study we tested the longstanding assumption that one out of every five people in hospitals have delirium. Even I didn’t really believe that adage until we did this study, in which we found a delirium prevalence of approximately 18% in the general hospital population.3

As a consequence of additional delirium researchers, we’ve seen a gathering of studies regarding treatment of delirium. Many of those studies are focused on low-line or more benign and non-pharmacological approaches—treatments that are presumed to do no harm, such as reorientation techniques. We have also seen a slow gathering of pharmacological treatment studies. This has been a particularly contentious and tricky area, because even in the world of delirium researchers there are completely disparate viewpoints on what constitutes optimal pharmacologic care for delirium. This is especially so in the case of geriatricians, who tend to exercise extreme care with antipsychotics.

"We tested the longstanding assumption that one out of every five people in hospitals have delirium. Even I didn’t really believe that adage until we did this study, in which we found a delirium prevalence of approximately 18% in the general hospital population."

Many of the studies conducted during the past few years are prospective studies, which is not to say they’re placebo-controlled studies, and no pharmacological agent is licensed by any regulatory agency, including the FDA or the European Medicines Board, for actual treatment of delirium. This is a tricky area for clinicians. Yet we know that in the real world clinicians are using antipsychotics for delirium very regularly, and the gold standard has been haloperidol.

The present study is one of the ways in which we attempt to use this new research in ways to inform delirium care.1 We focused on 28 prospective studies of pharmacotherapy for delirium with a minimum number of 10 patients in any treatment arm. There also had to be a clear diagnosis of delirium. There were 13 single-agent studies, 15 comparison studies (of which 11 were randomized), and 2 placebo-controlled studies, which were underpowered and aren’t necessarily superior to the other studies. Of course, there is also a publishing bias of positive studies, and the prospective studies provide a lower level of evidence, but that evidence is still useful. It not only gives us an idea of the existing evidence but it also addresses questions apart from whether drugs actually work for delirium. For example, some drugs clearly work for some patients, but why? What are the various presentations of delirium, and how can we improve the risk-benefit analysis? What is revealed about the different presentations of delirium, and at what point should we start using medications?

PP: What was the typical treatment setting across the 28 studies included in this paper?

DM: Geriatric medicine and geriatric psychiatry were the two best represented treatment settings. Of the agents studied, haloperidol was the best represented, although more recent studies are likely to focus on atypical antipsychotics. Other agents included chlorpromazine, olanzapine, risperidone, quetiapine, aripiprazole, amisulpiride and perospirone. About the same number of patients have been studied with the atypical antipsychotic agents as for haloperidol.

PP: What do we know about the pathophysiological markers of delirium? Are they well defined?

DM: First of all, what we know about the underlying neurobiology of delirium is limited. The prevailing theory is one of imbalance between dopamine and acetylcholine—specifically, excessive dopaminergic activity and hypocholinergicity. The actual evidence to support that theory is quite modest, and most of it derives from drug treatment studies, which is not the best way to get the evidence.

Delirium pathogenesis is certainly not restricted to neurochemical mechanisms. In recent decades, we have seen the mind and the body coming together more and more. In the case of delirium, it is remarkable that a kidney infection, for example, can spark a reactive pathology that can eventually cause someone’s brain to fail. Delirium is a fascinating condition from that perspective. Not surprisingly, studies are increasingly focusing on neuroinflammatory and stress axis mechanisms as key elements in delirium pathogenesis.

"One study reported that older medical patients are 11% more likely to experience mortality for every additional 48 hours of active delirium, so finding a balanced approach to pharmacotherapy for delirium may be more critical than previously perceived."

In terms of heterogeneity of delirium presentation, the standout point is that nearly half of delirium cases have an underlying dementia. Our understanding of this relationship between delirium and dementia has become considerably complicated over the last 5–7 years. There is a historical presumption that delirium is a harbinger of an emerging dementia, or of dementia that is becoming more progressive. There are cases, however, where people who are dementia-free (according to extensive neuropsychological testing) experience delirium, perhaps because they went through a deliriogenic stimulus, such as major surgery, and subsequently experience long term persistent cognitive difficulties. This raises a very interesting question: could delirium be a risk factor for dementia? I think there is a growing sense among clinicians and researchers in the delirium world that there may be some truth to that.

One of the things this paper highlights is the lack of good evidence examining the extent to which the presence of comorbid dementia predicts treatment response for delirium. What limited evidence does exist suggests that comorbid dementia leads to a reduced treatment response.

In terms of overall treatment response rates for delirium, the antipsychotics most commonly represented in our analyses had similar response rates, including olanzapine (73% response rate), haloperidol (74%), and risperidone (78%). Quetiapine (84% response rate) was the only antipsychotic included in any placebo-controlled analyses and had the highest response rate in our paper. The atypical antipsychotics had a predictably lower incidence of extrapyramidal symptoms (ranging from 3%–4%) compared to haloperidol (22%). Haloperidol was, however, associated with the lowest rate of sedation when compared to the atypical antipsychotics.

PP: Are you suggesting that untreated delirium could be a risk factor for dementia greater than that risk posed by treated delirium?

DM: I don’t usually think of it in those terms, but that’s a very nice way of thinking about it. There are some interesting studies showing that intensity of delirium is a predictor of a range of poor outcomes, such as high healthcare costs, and diminished functional ability.4 One study reported that older medical patients are 11% more likely to experience mortality for every additional 48 hours of active delirium, so finding a balanced approach to pharmacotherapy for delirium may be more critical than previously perceived.5

PP: In instances where pharmacotherapy—especially an antipsychotic—is selected for treating delirium, how long is treatment required in order to be effective?

DM: The typical time frame for treating delirium with an antipsychotic is 5–7 days, perhaps 5–10 days at times, but rarely does treatment for delirium go beyond that. It’s hard to justify delirium treatment exceeding that length of time. One of the things we highlighted in our paper is that, among those who respond to treatment, the vast majority of treatment response occurs within the first 3–5 days of treatment.

That’s a reasonably comfortable position for me to take, to support more active use of antispychotics for treating delirium. But again, given that 50% of people with delirium have an underlying dementia,3 it is important to note that the risk of cerebrovascular events associated with antipsychotic use in patients with dementia is increased, including during the early part of treatment. So it certainly appears that some of the findings in relation to increased risk of stroke and other events do apply even in short-term use in people with delirium.